• Detection of Brain Hypoxia-Ischemia and Neuroprotection

    Due to the brain’s limited ischemic tolerance, even relatively brief episodes of inadequate delivery of oxygen (hypoxia) as well as impaired oxygenation and blood flow (hypoxia-ischemia) may result in the breakdown of structural integrity and impairment of brain function. The resultant brain damage may affect neonates and infants during birth asphyxia, during perioperative adverse events, such as hemodynamic instability and cardiopulmonary arrests, or during neurosurgical operations or open-heart procedures involving cardiopulmonary bypass. Long-term sequelae include neurobehavioral abnormalities, motor deficiencies, learning impairment and seizures. Exposing this dilemma, persisting developmental abnormalities have been documented in up to 50 percent of survivors of complex neonatal cardiac surgery. However, the exact threshold for inadequate oxygenation and / or blood flow to cause long-term impairment is not well known. Moreover, effective neuroprotective strategies during these periods of brain ischemia are lacking.

    Neuroprotection - Pharmacological Approach

    Anesthetics are frequently used in the perioperative setting. Their diverse mechanisms of action, which include interactions with sodium, potassium and calcium channels, acetylcholine, serotonin, aminobutyric acid, glycine and glutamate receptors, as well as signaling proteins, make them interesting targets as neuroprotectants. In facet, neuroprotective properties have been repeatedly observed for several anesthetics in models of the adult brain. It remains controversial, however, whether anesthetics can confer protection during severe ischemic insults and whether neuroprotection can be sustained beyond the immediate post-ischemic period.

    Significant differences exist between the adult and the immature brain regarding susceptibility and effects of brain ischemia, suggesting the possibility for a differential response to protective strategies. Accordingly, we are investigating the effects of anesthetics during brain ischemia on neuronal structure as well as long-term neurocognitive function in the immature brain.

    We have demonstrated protective effects of the inhaled anesthetic Desflurane in models relevant to congenital heart surgery and hypothermic cardiopulmonary bypass and have more recently studied Sevoflurane as a protective adjuvant during neonatal brain ischemia. This area of research is led by Dr. Erica Lin.

    Neuroprotection - Preconditioning

    Ischemic preconditioning is a powerful form of endogenous protection, during which transient, brief periods of ischemia can protect against subsequent, injurious episodes of conditions. However, local preconditioning cannot be used for the brain due to the risk of injury, even during the brief periods of precondition. However, applying the same ischemic stimulus to distant organs or tissue (termed remote ischemic preconditioning) may also provide neuroprotection. Accordingly, the aims of this research are to examine the use of remote ischemic precondition for protection of the immature brain during hypoxia and ischemia, to delineate the appropriate dose and timing, and to test long-term cognitive outcomes. The overall goal of this research is to harness the body's endogenous protective capabilities against injury, thereby devising a simple and cost-effective strategy to improve neurological outcome folllowing brain ischemia early in life. The group leader for this project is Dr. Christopher Lee.

  • Desflurane significantly reduces neurological disability at 48 h following low-flow cardiopulmonary bypass.

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  • Desflurane significantly decreases neuronal damage in several brain regions.

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  • Performance in hidden platform probe trials in the Morris water maze was impaired in adult mice following neonatal brain ischemia, compared with littermates treated with a combined protective strategy. Bars represent mean dwell times and standard errors in the quadrant of the hidden platform after its removal (A), a measure of spatial memory retention, and the number of transitions across the previous platform location (B), a measure of spatial memory accuracy. All animals underwent right carotid artery ligation on postnatal day 10 and exposure to 10% oxygen for 60 min, without (HI, black bars) or with peri-ischemic hypothermia and sevoflurane (HI-Protect, gray bars), except for Room Air animals (white bars), which only underwent carotid artery ligation without hypoxia.

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